The present invention relates generally to treatments for atherosclerosis. More specifically, the present invention relates to methods of reducing the risk of atherosclerosis.
Cardiovascular disease is the leading cause of death in the United States. In the United States, of a population of 226.5 million in 1980, 551,400 died of ischemic heart disease and 169,500 died of cerebrovascular causes related to arterial disease. See Merck Manual, 15th Edition, p. 386.
Atherosclerosis is a form of arteriosclerosis marked by the formation of atheromas. The disease causes the lumen of an artery to become narrowed or blocked (occluded). The atheroma obstructs circulation by protruding into the arterial lumen. The narrowing of the artery restricts blood flow to the organ that is nourished by the artery. The reduced blood flow results in a deterioration of the organ to the point wherein the organ can be permanently damaged unless the blockage of blood flow is removed. When an artery that serves the heart is narrowed or blocked, the pathological process results in a heart attack.
The relationship between hypercholesterolemia, abnormal lipoprotein profiles, and atherogenesis has been well defined. A major risk factor of atherosclerosis is elevated serum lipids. See Merck Manual, 15th Edition, p. 386. Studies have also demonstrated that elevated levels of high density lipoproteins (HDL) - cholesterol are negatively correlated to the incidence of coronary heart disease. See, Yamashita et al, "Accumulation of Apolipoprotein E-Rich High Density Lipoproteins in Hyperalphalipoproteinemic Human Subjects with Plasma Cholesterol Ester Transfer Protein Deficiency", Journal of Clinical Investigation, Vol. 86, September 1990, 688-695.
Cholesterol is an essential component of the membranes of every human cell, necessary for tissue repair and other functions. The amount of cholesterol entering the circulation each day, however, greatly exceeds the essential requirements. There is no system for the cholesterol catabolism in the peripheral tissues. Accordingly, excess cholesterol arriving at the periphery must be returned to the liver if it is to be eliminated. The process by which the cholesterol is returned to the liver is termed "reverse cholesterol transport." High-density lipoprotein has been implicated in reverse cholesterol transport. See, Cholesterol Ester Transfer Protein, The Lancet, Vol. 338, Sep. 14, 1991, pp. 666-667.
Although HDL levels are known to be decreased by obesity, cigarette smoking, male sex, and diets high in polyunsaturated fat, the mechanisms of variations of HDL levels in populations are poorly understood. Inazu et al, "Increase High-Density Lipoprotein Levels Caused By A Common Cholesterol-Ester Transfer Protein Gene Mutation", The New England Journal of Medicine, Nov. 1, 1990, p. 1234-1238.
In vivo, cholesterol ester transfer protein is believed to be central to cholesterol transport in human plasma. Despite the potential benefits of the cholesterol pathway, in terms of control and regulation of cholesterol transport, there is considerable disadvantage because cholesterol ester transfer protein can convert the non-atherogenic HDL into VLDL. VLDL is the precursor for LDL that has been strongly implicated in the pathogenesis of atherosclerosis. It has been reported that the combination of sodium oleate and CETP promotes a major redistribution of cholesterol ester from HDL to LDL. See, Barter. "Enzymes Involved in Lipid and Lipoprotein Metabolism", Current Opinion in Lipidology, 1990, 1:518-523. See also, Brown et al. "Molecular Basis of Lipid Transfer Protein Deficiency in a Family With Increased High-Density Lipoproteins", Nature, Vol. 342, Nov. 23, 1989, pp. 448-451 ("[t]he plasma cholesterol ester transfer protein (CETP) catalyses the transfer of cholesterol ester from HDL to other lipoproteins and therefore might influence HDL levels.").